Amyotrophic lateral sclerosis (ALS) is an adult-onset lethal disorder characterized by degeneration of brain and spinal motor neurons. Approximately 10% of ALS cases are the direct result of genetic inheritance; a subset of these is the result of mutations in the Cu-Zn superoxide dismutase (SOD1) gene. For the remaining 90% of cases, the underlying pathogenic mechanisms remain unknown. It is hypothesized that genetic susceptibility combined with specific lifestyle elements including exposure to environmental toxins contribute to the development of sporadic amyotrophic lateral sclerosis. No treatment is currently available to significantly slow or halt the progress of this disease. Transgenic mice overexpressing mutant SOD1 exhibit an autosomal dominant adult onset degeneration of the motor system which bears a striking resemblance to amyotrophic lateral sclerosis, both clinically and pathologically. They provide an excellent opportunity to study the disease process prior to the age when overt symptoms appear, particularly because the phenotype follows a well-characterized and predictable course. The transgenic mice have been utilized for preclinical trials of a large number of putative therapeutic agents. However, these mice do not adequately reflect the heterogeneity both in genetic backgrounds and in environmental exposures of human ALS patients. Extensive phenotypic and genotypic diversity does exist between inbred strains of mice. We now propose to take advantage of this diversity to create models of ALS which represent a greater variation in phenotypic presentation. Specifically, we aim to: 1) Breed the G93A mutant SOD1 trait into 6 distinct genetic strains of mouse; 2) Measure clinical parameters including age at onset of symptoms, motor and sensory functions, and endstage disease; and 3) Examine markers of spinal motor neuron degeneration and glial activation/inflammatory processes at intervals prior to and following the appearance of symptoms. We expect that modifier genes expressed in the various inbred strains will alter the phenotype of the disease, yielding mice with different ages of onset, different disease courses, and at the cellular level, different degrees of involvement of inflammatory processes and pathways of motor neuron death. The overall objective of this R21 is the creation and characterization of models of ALS in which a known disease-causing gene is expressed in the presence of widely varying genetic backgrounds, thus providing a more realistic range of disease phenotypes for testing relative vulnerability to exposure to environmental toxins, and ultimately for identifying genes which contribute to specific vulnerability or resistance to deleterious environmental agents.